APPLICANT'S ABSTRACT: Alcoholics are almost invariably heavy smokers and smoking enhances alcohol use, but explanations for these interactions are lacking. Observations made in our laboratory indicate that chronic nicotine treatment results in tolerance to ethanol, reverses enhanced excitability seen in ethanol-withdrawing mice, and nicotine increases ethanol self-selection in a two-bottle choice experiment have been seen. The experiments described in this proposal will build on these observations by assessing whether three commonly-used inbred mouse strains differ in these interactions. Since ethanol affects the activity of "peripheral-type" nicotinic receptors (nAChRs) found in the electric organ of Torpedo californica, particularly activation and desensitization, the effects of ethanol on brain (nAChR) function will be assessed using several neurochemical assays that we have developed which can monitor the activation and desensitization of several different (nAChRs). Preliminary data suggest that some of the brain (nAChR) subtypes are resistant to ethanol whereas others, particularly alpha-7-containing, are inhibited by low concentrations of ethanol. Effects of in vitro and chronic in vivo ethanol on activation, desensitization, and recovery from desensitization of several types of brain (nAChRs) will be measured. Some of the chronic treatment experiments will involve short-term/high-dose treatments (1-2 weeks) while others will use long-term (6-8 months) treatment. The chronic studies will build on our observation that chronic nicotine treatment results in a long-term desensitization of brain (nAChRs) in some brain regions, and not in others. Hopefully, these studies will provide a rigorous test of the hypothesis that some of the basis of the co-abuse of ethanol and nicotine arises because of interactions between these two drugs at brain (nAChRs).